A whole set of new genes associated with body fat distribution and obesity have been identified in two major studies by
an international team of researchers, including the largest study yet of DNA variation across our genomes involving
almost a quarter of million people.

The group has identified 13 new gene regions where variations in DNA sequence can be linked to whether we are
apple-shaped or pear-shaped. The majority of these variations have a markedly stronger effect in women than in men.

The scientists, led by researchers at Oxford University and the Medical Research Council (MRC) Epidemiology Unit in
Cambridge, have also found 18 new genetic variations associated with increased susceptibility to obesity.

The results, published in Nature Genetics, give greater insight into the biological processes that can lead to
obesity and that are involved in determining body fat distribution. The work immediately opens up new avenues of
research into the biological basis of obesity, but it is possible that such understanding could in time guide the
development of new ways of preventing or treating obesity.

"These large studies focusing on common variants have identified important links between common DNA
variants and obesity/fat distribution," says Dr Inês Barroso, from the Wellcome Trust Sanger Institute and
a senior author on the papers, "but the next big challenge will be to understand the underlying
biological and physiological pathways affected by those variants. In part, this increasing understanding will be helped
by the overlap between the findings we have made, based on relatively small effects, in many thousands of samples
compared with the results from much less common, severely affected people."

"In this exciting work, we have found possible new links between DNA variation and obesity/fat distribution but the
next few years promise to be just as exciting as we embark on studies of rare variants."

Apples and pears

Where we store fat in our bodies can influence our health. More fat around our waists (being apple-shaped) is
associated with increased risk of type 2 diabetes and heart disease, even after correction for obesity. In comparison,
storing fat in thighs and bums (being pear-shaped) has been suggested in some research to offer some protection against
diabetes and high blood pressure.

Our waist-to-hip ratio is a good measure of this difference in body fat distribution, and is known - like
predisposition to obesity - to be determined to some extent by the genes we inherit.

There are also clear differences in body shape between men and women, but the body processes that determine these
differences are not well understood.

" We have found possible new links between DNA variation and obesity/fat distribution but the next few years
promise to be just as exciting as we embark on studies of rare variants. "

Dr Inês Barroso

The researchers completed a large genome-wide search for DNA variations that could be connected to waist-to-hip ratios.
They identified 13 new gene regions linked to body fat distribution, and confirmed the one previously known genetic
link. They show that these genetic variations affect waist-to-hip ratio distinct from any effect on overall obesity.

Seven of the identified genetic variations have much stronger effects in women than in men, suggesting they may
underlie some of the difference in fat distribution between the sexes.

Although the gene regions identified explain only around one per cent of the variation in waist-to-hip ratios in the
population, they do point towards specific biological mechanisms that are involved in regulating where the body stores
fat. The regions implicate genes involved in regulating cholesterol, triglyceride levels, insulin and insulin
resistance.

"By finding genes that have an important role in influencing whether we are apple shaped or pear
shaped, and the ways in which that differs between men and women, we hope to home in on the crucial underlying
biological processes," says Dr Cecilia Lindgren of the Wellcome Trust Centre for Human Genetics at Oxford
University, senior researcher on the waist-to-hip ratio study and who was involved in both papers.

"Understanding biology through finding genes is just a first step in a long journey towards treatment, but it is a
vital one. As efforts to tackle obesity through changes in lifestyle or by different treatment options have proved
extremely challenging, the potential to alter patterns of fat distribution may offer an alternative for future drug
discovery."

Genes and obesity

The second study looked for genes connected to body mass index (BMI). BMI is a measure commonly used to classify adults
as being overweight (BMI of 25-29.9) or obese (BMI of 30 or greater). The discovery of 18 new genetic regions has more
than doubled the DNA variations reliably linked to BMI to 32.

Some of the new findings indicate the involvement of genes active in the brain that influence our appetite and also
genes involved in the control of insulin levels and metabolism.

The study also showed that people who inherit many of the BMI-increasing DNA variants from their parents weigh 7-9 kg
more than those who inherit few of these variants; this difference in weight is solely due to the fact that they differ
genetically. Despite the large difference between the most susceptible and least susceptible, together the 32 confirmed
genetic associations still only explain 1.45% of the variation seen in people's BMIs, suggesting there are many more
genetic associations still to be found.

"We have conducted the largest ever genome-wide association study so far, and by including almost
250,000 individuals we have been able to identify 18 new genetic regions associated with obesity," says Dr Ruth
Loos of the MRC Epidemiology Unit in Cambridge, senior researcher on the BMI study and who was involved in both
studies.

"These two studies are the beginning of new insights into to biology of obesity and body shape, which in turn may lead
to more targeted approaches to obesity prevention and potentially to the development of new drugs. But we should not
forget that, while the genetic contribution to obesity is substantial, a large part of obesity susceptibility remains
down to our lifestyle."

The studies were carried out by the GIANT (Genetic Investigation of Anthropometric Traits) consortium, an international
collaboration of more than 400 scientists from 280 research institutions with support from many funding agencies
worldwide.

Notes to Editors

Waist-hip ratio paper

The study of waist-hip ratio began by combining data from 32 genome-wide studies included over 77,000 participants of
European ancestry. The researchers looked for individual DNA changes at over 2.85 million positions across their
genomes that could reliably be linked with body fat distribution. The identified gene regions with the strongest
associations were then checked with data from a further 29 studies including over 113,500 separate individuals. This
revealed 14 gene regions associated with waist-hip ratio, adding 13 new regions and confirming the one previously known
association. Seven of the identified genetic variations have much stronger effects in women than in men, suggesting
they may underlie some of the difference in fat-distribution between the sexes.

Body mass index paper

The study of genetic determinants of body mass index combined data from 46 studies involving a total of 123,865 people.
The genome-wide scans looked for DNA variations at around 2.8 million positions along the genome that were associated
with BMI. The genetic regions with the strongest associations were then looked at in a further data set including
almost 126,000 individuals. The combined analysis including almost ¼ million people found 32 genetic regions
associated with body mass index, confirming 14 genetic variations known to be linked to obesity susceptibility and
adding 18 new ones.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

Funding

A full list of funding agencies is available on the Nature Genetics website.

Participating Centres

The studies were carried out by the Genetic Investigation of Anthropometric Traits (GIANT) consortium. A full list of
participating centres is available on the Nature Genetics website.

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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